16-diazo estrone ethers and preparation thereof



United States Patent Apr. is, 1352, Ser. No. 187,225

or a ea- 391.4

This invention relates to novel organic compounds of the following structural formula, pharmaceutical compositions thereof, and to novel methods for the preparation of the compounds:

This compound is useful as an intermediate for the preparation of lo-halo-estrones, such as, low-fluoroestrone, lofi-tluoro-estrone and the corresponding 16aand 16,8-chloro-, iodo-, and bromo-estrones.

The compounds of the above formula are also useful as potent lipid-shifting agents without feminizing effects and are useful in the treatment of inflammatory diseases, disturbances in sodium retention and Water balance in the body of animals utilizing sodium in the hydrostatic system, adrenal gland malfunctions, and abnormal mental and central nervous system behavior.

The compounds can be administered in conventional unit dosage form, admixed with conventionally acceptable pharmaceutical carriers or diluents, such as, lactose, calcium carbonate, starch, sucrose, and the like and can be prepared in the form of pills, capsules, tablets, oluses, feeds, powders, and the like. The compounds can also be administered parenterally when prepared in suitable media for injection in accordance with known methods of preparing anti-inflammatory steroidal hormonal compounds for this purpose.

In the formula above, R is a lower-alkyl or cycloalkyl group contm'ning from 1 to 8 carbon atoms as, for example, methyl, ethyl, propyl, butyl, isobutyl, cyclopentyl, hexyl, cyclohexyl, 2,2-dimethylhexyl, n-octyl and the like.

The preparation of the novel compounds of this invention can be accomplished using estrone-S-alkyl ethers and transforming these to the corresponding oximino compounds by reaction with an alkyl nitrite, such as, butyl nitrite. The reaction is carried out preferably in an alkaline alkanol reaction mixture. The 16-oximino compound thus produced is converted to the corresponding l6-diazo compound by reaction with chloramine or its chemical equivalent, such as a mixture of ammonia and an alkali metal hypochlorite. The reaction is carried out preferably in a partly aqueous solution.

The following specific examples are illustrative of the invention.

Example J.-16-0ximin0-3-Meth0xy-1,3,5 (10)- i Estratrienl 7-One To a suspension of 20.77 g. estrone-3-methylether in 150 ml. potassium tertiary butoxide and 50 ml. of tertiary butyl alcohol was added ml. of butyl nitrite. After stirring under N at 40 C. for 18 hours, a mixture of ice and water was added. After one extraction with ether, the aqueous solution was brought to pH 3-4 with acetic acid, whereupon the product precipitated. Yield of 18.89 g., 91 percent, melting at 165171 C.

Patented June 2, i964 ice with decomposition. Recrystallization from methanol brought the melting point to l83.5l C.

Example 2.] 6-Diaz0-3-Methoxy-1 ,3,5 (10) Estmtrien-I 7-One To a stirred mixture of 6.2 g. l6-oximino-3-methoxy- 1,3,5(10)-estratrien-17-one, produced in Example 1, 25 ml. one normal sodium hydroxide, 206 ml. of water and 300 ml. die'thyl ether at 9-3 was added 5 ml. ammonium hydrox de. Keeping the temperature at 0-5 C., 70* ml. Clorox (sodium hypochlorite) was added dropwise over a period of 20-30 minutes. After stirring for 6 hours at 0-5", the ether layer was separated. The aqueous layer was extracted with 3-100 ml. portions of ether. The combined ether solutions were dried and then evaporated to dryness. Yield 3.5 g., Ml. 141.5- 144 C. Recrystallization from ether gave 1.75 g., MP. 143-145 C. Infrared analysis showed characteristic diazoketone absorptions.

Estrone E-ethyl ether, estrone 3-propyl ether, and estrone S-cyclopentyl ether can be substituted for estrone S-methyl ether in the procedure of Example 1 to produce respectively as a light colored crystalline product, 16 oximino-3-cthoxy 1,3,5(10)-estratrien-l7-one, 16- oximino 3-propoxy 1,3,5(l0)-estratrien-l7-one, and 16 oximino-S-cyclopentyloxy l,3,5(lO)-estratrien-l7- one.

These three products can be substituted in place of 16- oximino-3-methoxy-1,3,5 (l0)-estratrien-17-one in the procedure of Example 2 to produce respectively as a light colored crystalline product 16-diazo-3-ethoxy-1,3,5(l0)- estratrien-17-one, 16 diazo-3-propoxy-l,3,5(ND-estratrien-17-one, and l6-diazo-3-cyclopentyloxy-1,3,5(l0)- estratrien-l7-one, each showing infrared analyses with characteristic diazo ketone absorptions.

The l-diazo compounds of this invention can be reacted with hydrogen fluoride or other hydrogen halide in accordance with the procedure of Reich and Reichstein, Helvetica Chimica Acta, 22, 1124 (1939) to produce the corresponding l6-fluoro or other 16-halo products. The lficz-halo and 16B-hflo epimers can be separated from the reaction mixture by known methods, such as, chromatography, selective crystallization or counter current extraction, and the like. The 1604- iluoro or 16,8-fiuoro or other 16-halo compounds, e.g., 16,8-fiuoro 3-methoxy 1,3,5(10-estratrien-17-one, 16ozfluoro-3-methoxy-1,3,5(10)-estratrien 17 one possess gonadctropic inhibiting and lipid regulating activity and are useful in the treatment of hypercholesterolemia, and can be administered in the form of oral tablets.

I claim:

1. A compound of the formula:

th ill References Cited in the file of this patent Cava et al.: Journal of American Chemical Society, Jan. 5, 1962, vol. 84, pages -116 relied on. 

1. A COMPOUND OF THE FORMULA: 